SUMMARY OR WORK: The ultimate goals of this project are to determine how arterial stiffness properties influence myocardial structure and function and contribute to cardiovascular morbidity and mortality. 1. We have recently discovered, in cross-sectional studies, that estrogen replacement therapy (ERT) in postmenopausal women reduced blood pressure (BP) and the age-associated increase in arterial stiffness and that the addition of progestins to ERT appeared to reduce these beneficial effects. In a second study, 226 healthy, normotensive postmenopausal women from the Baltimore Longitudinal Study of Aging with a mean (+SD) age of 64 + 10 years were followed for 5.7 + 5.3 years. Seventy-seven women used both estrogen and progestin (HRT users), and 149 used neither. Over time, average systolic blood pressure (SBP) increased less in HRT users than nonusers, independent of other cardiovascular risk factors, physical activity and alcohol use. Thus, postmenopausal women taking HRT have a smaller increase in SBP over time than those not taking HRT. This difference is intensified at older ages. 2. To examine the role of nitric oxide (NO) synthesis on BP changes during salt loading in postmenopausal women, we measured asymmetric dymethylarginine (ADMA), a potent endogenous inhibitor of NO synthesis before and after 4-7 days of low-salt (70mEg/day) or high-salt (260mEg/day) diet in 12 postmenopausal women. Sodium sensitivity of 24 hour ambulatory SBP and pulse pressure correlated with change in ADMA from low- to high-salt intake, after adjustment for age. These findings suggest that inhibition of NO synthesis contributes to the BP increase during high salt intake in postmenopausal women. 3. To determine whether growth hormone or sex steroid supplementation ameliorates arterial stiffness properties in older hormone-deficient adults, we measured PWV and AGI in men and women aged 65 years and older, before and after hormonal replacement. 4. The reproducibility of aortic pulse wave velocity (APWV) was evaluated in a population-based study of cardiovascular disease in the elderly. The results indicated that the mean PWV is reproducible even when sonographers and readers are newly trained. 5. The Activity Counseling Trial (ACT) employed various patient education and counseling interventions to increase physical activity in sedentary primary care populations. APWV and coronary risk factors were measured pre- and post-intervention. Pre-intervention, older age was associated with stiffer vessels and a higher HDL cholesterol with more elastic ones. HDL cholesterol may be an indirect indicator of aerobic capacity or of less atherosclerosis, suggesting mechanisms for preserving vascular integrity. 6. We are testing the hypothesis that 1-2 years of home-based aerobic exercise training can reduce arterial stiffness in the multicenter NIH-sponsored Activities Counseling Trial of 810 subjects 35-75 years old. 7. The association between vascular stiffness and body fat was evaluated in 2488 older adults (mean age 74 years, 52% female, 40% Black) enrolled in Health ABC, a prospective study of disability in the elderly. Independent of age and BP, PWV was positively associated with weight, abdominal circumference, abdominal subcutaneous fat, abdominal visceral fat, thigh fat area, total fat and higher levels of glucose, insulin and hemoglobin A1c (p < .001 for all). The strongest association was with abdominal visceral fat. In multivariate analysis, independent positive associations with PWV were age, SBP, heart rate, abdominal visceral fat, smoking, hemoglobin A1c, and history of hypertension. The association between PWV and abdominal visceral fat was consistent across tertiles of body weight. Thus, keeping weight (specifically visceral fat) within normal limits through the advancing years may slow the process of vascular aging, possibly reducing the associated risks. 8. Arterial stiffness was measured in the Pittsburgh, PA site for the Cardiovascular Health Study Cross-sectional results indicate that risk factors associated with the insulin resistance syndrome (hypertension, hyperglycemia, hyperinsulinemia, and abdominal distribution of body fat) are associated with arterial stiffening in older adults. Long-term follow-up of this cohort will allow us to examine the prognostic significance of arterial stiffness in an older population. 9. Nonenzymatic glycosylation and cross-linking of proteins by glucose contributes to an age-associated increase in vascular and myocardial stiffness. Some recently synthesized thiazolium compounds selectively break these protein cross-links, reducing collagen stiffness. We investigated the effects of 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711) on arterial and left ventricular (LV) properties and their coupling in old, healthy, nondiabetic Macaca mulatta primates (age 21 + 3.6 years). ALT-711 improved both arterial and ventricular function and optimized ventriculo-vascular coupling, suggesting that it may be an effective agent to improve impaired cardiovascular function that occurs in the context of heart failure associated with aging, diabetes, or hypertension, conditions in which arterial and ventricular stiffness are increased. 10. We tested whether ALT-711, a novel nonenzymatic breaker of advanced glycation end-product crosslinks, selectively improves arterial compliance and lowers pulse pressure in older individuals with vascular stiffening. Nine US centers recruited and randomly assigned subjects with resting arterial pulse pressures > 60 mm Hg and systolic pressures > 140 mm Hg to once-daily ALT-711 (210 mg; n= 62) or placebo (n = 31) for 56 days. Preexisting antihypertensive treatment (90% of subjects) was continued during the study. The results show that ALT-711 improved total arterial compliance in aged human with vascular stiffening, and it may provide a novel therapeutic approach for this abnormality, which occurs with aging, diabetes, and isolated systolic hypertension. 11. We are attempting to identify genetic factors contributing to exaggerated arterial stiffness and arterial intima-medial thickness in a Sardinian population (a "founder population", relatively genetically homogenous compared to "outbred" populations) and to determine whether these factors enhance the predictive accuracy for overall cardiovascular risk, when added to a standard cardiovascular risk profile. R&D contract awarded (D. Schlessinger, Project Officer) 12. Although the geometry of small arteries and arterioles affects their distensibility, the functional correlates of different geometric phenotypes of large arteries have not been characterized in a community based population. We therefore characterized the distribution of carotid arterial geometric phenotypes, their functional correlates, and relationships to gender, age, body size, BP and other measured hemodynamic variables in an older adult populations . The prevalence of specific CGPs in the total sample was: 83.4% for CGP1 (normal), 5.5% for CGP2 (increased wall thickness with normal mass), 2.2% for CGP3 (normal thickness with increased mass), and 8.9% for CGP4 (increased wall thickness with increased mass). Compared to CGP1, all deviant CGPs had increased carotid resistance and had higher CCA circumferential wall stress. Each deviant CGP is characterized by a unique combination of increased circumferential wall stress, with variable FSS, strain, distensibility, central BP, and late pressure augmentation